ABSTRACT Primary progressive aphasia (PPA) is one of the clinical presentations of the frontotemporal dementia- spectrum disorders. It occurs when neurodegeneration selectively targets the language networks of the brain. Discoveries from previous cycles of this PPG were fundamental in characterizing PPA and its main clinic- anatomical presentations: the nonfluent/agrammatic (nfvPPA), semantic (svPPA) and logopenic (lvPPA) variants. These three syndromes are associated with specific patterns of language and anatomical damage, and are each thought to have different probable underlying molecular causes. Despite these significant advances in PPA characterization, many questions regarding clinical heterogeneity, prognosis and biological basis remain unanswered. In this project, we will take advantage of the wealth of multidisciplinary expertise and data available through this PPG to investigate differential diagnosis, clinical and neuroimaging progression and in-vivo pathological prediction in PPA. We propose a five-year cross-sectional and longitudinal study of the cognitive, anatomical and biological features of more than 100 newly recruited individuals with PPA. We will use the most modern techniques, from computerized, tablet-based cognitive tests to molecular neuroimaging and gene expression, to develop principles and diagnostic concepts that can also be applied in less specialized settings. In particular, in Aim 1 we will use validated and tablet-based tests of visuo-spatial, executive and socio-emotional functions to study non-language features in the PPA variants. We hypothesize that specific patterns of cognitive dysfunction will be found in each PPA variant at presentation and at 1-year follow-up, depending on the anatomical network involved. In Aim 2, we will use the human healthy connectome architecture to predict longitudinal neuroimaging changes in PPA. Based on the transynaptic-spread theory of neurodegeneration, we hypothesize that regions strongly connected to syndrome-specific epicenters will show atrophy and molecular PET changes at one-year follow-up. Finally, in Aim 3, we will combine clinical, neuroimaging, genetic and pathological data in the largest and most comprehensive PPA dataset ever examined, in a multivariate analyze that will determine whether molecular diagnosis can be predicted in-vivo. This project will provide crucial data for the diagnosis of neurodegenerative diseases in their early stages, when treatment can be most effective.